背景:肥胖与慢性腹泻的风险显著增加有关,这已被提议为灵沪的肥胖-腹泻综合征(ODS);然而,其分子机制在很大程度上是未知的。
目的:揭示参与ODS的空肠转录组变化。
方法:在6名ODS患者(JOD组)的队列中,6名无腹泻的肥胖者(JO组),和6名健康对照(JC组),我们进行了高通量测序和生物信息学分析,以鉴定空肠粘膜mRNA表达改变和功能失调的生物学过程.在另一组16名ODS患者(SOD组)中,16名无腹泻的肥胖者(SO组),和16名健康对照(SC组),检测血清二胺氧化酶(DAO)和D-乳酸(D-LA)浓度以评估肠屏障功能的变化。
结果:JO组和JC组空肠黏膜基因表达谱相似,只有1个差异表达基因(DEG)。JOD组的基因表达谱有显著变更,与JO组相比有411个DEG,与JC组相比有211个DEG,129重叠。对这些DEGs的富集分析表明,消化等生物过程,吸收,在JOD组中,营养物质(尤其是脂质)的运输倾向于上调,而rRNA加工等生物过程,线粒体翻译,抗菌体液反应,DNA复制,在JOD组中DNA修复倾向于下调。八个DEG(CDT1,NHP2,EXOSC5,EPN3,NME1,REG3A,PLA2G2A,和PRSS2)可能在ODS的病理过程中起着关键的调节作用,其表达水平在ODS患者中显著降低(P<0.001)。在第二个队列中,与健康对照相比,所有肥胖个体血清肠屏障功能标志物(DAO和D-LA)水平均显著升高(P<0.01),但SOD组高于SO组(P<0.001)。
结论:与健康对照组和无腹泻的肥胖者相比,令虎ODS患者空肠粘膜有广泛的转录组变化,可能影响肠道屏障功能,从而导致肥胖和慢性腹泻表型。
BACKGROUND: Obesity is associated with a significantly increased risk for chronic diarrhea, which has been proposed as Linghu\'s obesity-diarrhea syndrome (ODS); however, its molecular mechanisms are largely unknown.
OBJECTIVE: To reveal the transcriptomic changes in the jejunum involved in ODS.
METHODS: In a cohort of 6 ODS patients (JOD group), 6 obese people without diarrhea (JO group), and 6 healthy controls (JC group), high-throughput sequencing and bioinformatics analyses were performed to identify jejunal mucosal mRNA expression alterations and dysfunctional biological processes. In another cohort of 16 ODS patients (SOD group), 16 obese people without diarrhea (SO group), and 16 healthy controls (SC group), serum diamine oxidase (DAO) and D-lactate (D-LA) concentrations were detected to assess changes in intestinal barrier function.
RESULTS: The gene expression profiles of jejunal mucosa in the JO and JC groups were similar, with only 1 differentially expressed gene (DEG). The gene expression profile of the JOD group was significantly changed, with 411 DEGs compared with the JO group and 211 DEGs compared with the JC group, 129 of which overlapped. The enrichment analysis of these DEGs showed that the biological processes such as digestion, absorption, and transport of nutrients (especially lipids) tended to be up-regulated in the JOD group, while the biological processes such as rRNA processing, mitochondrial translation, antimicrobial humoral response, DNA replication, and DNA repair tended to be down-regulated in the JOD group. Eight DEGs (CDT1, NHP2, EXOSC5, EPN3, NME1, REG3A, PLA2G2A, and PRSS2) may play a key regulatory role in the pathological process of ODS, and their expression levels were significantly decreased in ODS patients (P < 0.001). In the second cohort, compared with healthy controls, the levels of serum intestinal barrier function markers (DAO and D-LA) were significantly increased in all obese individuals (P < 0.01), but were higher in the SOD group than in the SO group (P < 0.001).
CONCLUSIONS: Compared with healthy controls and obese individuals without diarrhea, patients with Linghu\'s ODS had extensive transcriptomic changes in the jejunal mucosa, likely affecting intestinal barrier function and thus contributing to the obesity and chronic diarrhea phenotypes.